Affinage

PYCR1

Pyrroline-5-carboxylate reductase 1, mitochondrial · UniProt P32322

Length
319 aa
Mass
33.4 kDa
Annotated
2026-04-28
85 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PYCR1 is a mitochondrial NAD(P)H-dependent pyrroline-5-carboxylate reductase that catalyzes the final step of proline biosynthesis and functions as a critical redox valve by oxidizing NADH to sustain TCA cycle activity, particularly under hypoxia (PMID:35108535, PMID:29562167, PMID:34291342). The enzyme forms decamers whose assembly and activity are regulated by SIRT3-mediated deacetylation at K228 (PMID:31108370), while protein stability is controlled through phosphorylation (ITPKA at S29 blocking Stub1-mediated ubiquitination) and BHLHE41-promoted proteasomal degradation (PMID:39170313, PMID:38811952); a nuclear pool phosphorylated at Y135 by IGF1R couples NAD+ production to SIRT7-dependent H3K18ac deacetylation at ELK4-target genes (PMID:37777542). Beyond its canonical mitochondrial role, PYCR1 drives collagen synthesis in cancer-associated fibroblasts through glutamine-to-proline flux (PMID:35760868), stabilizes EGFR via USP11-mediated deubiquitination (PMID:41254241), and interacts with DJ-1 and RRM2B to maintain mitochondrial integrity and redox defense (PMID:23743200, PMID:26733354). Loss-of-function mutations in PYCR1 cause autosomal recessive cutis laxa type IIIB, a progeroid connective tissue disorder linked to mitochondrial dysfunction and increased oxidative stress–induced apoptosis (PMID:19648921).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2009 High

    Establishing that PYCR1 is a mitochondrial enzyme whose loss causes mitochondrial dysfunction, oxidative stress sensitivity, and connective tissue disease resolved the long-open question of whether proline biosynthesis defects underlie progeroid cutis laxa.

    Evidence Subcellular fractionation, patient fibroblast functional assays, and morpholino knockdown in Xenopus/zebrafish

    PMID:19648921

    Open questions at the time
    • Precise mechanism linking PYCR1 loss to altered mitochondrial morphology not defined
    • Role of PYCR2 redundancy not yet addressed
  2. 2013 High

    Identification of DJ-1 as a direct binding partner that enhances PYCR1 enzymatic activity established a molecular link between Parkinson's-associated oxidative stress defense and proline metabolism.

    Evidence Reciprocal co-immunoprecipitation, in vitro binding, enzyme activity assay, and epistasis by double knockdown

    PMID:23743200

    Open questions at the time
    • Structural basis of DJ-1–PYCR1 interaction unknown
    • Physiological significance in neurodegeneration not tested in vivo
  3. 2014 High

    Demonstrating that PYCR1 also reduces P6C to L-pipecolic acid with comparable kinetics to P5C expanded the enzyme's substrate scope to lysine degradation.

    Evidence In vitro enzyme kinetics with LC-MS/MS product detection

    PMID:24431009

    Open questions at the time
    • In vivo contribution to pipecolic acid metabolism not confirmed
    • Relative flux through P5C vs. P6C in physiological settings unclear
  4. 2016 High

    Discovery that PYCR1/2 are components of RRM2B complexes and required for RRM2B's anti-oxidative stress function placed PYCR1 within a broader mitochondrial stress-defense network.

    Evidence Flag-RRM2B affinity purification with mass spectrometry, shRNA knockdown, oxidative stress viability assays

    PMID:26733354

    Open questions at the time
    • Direct vs. indirect nature of PYCR1–RRM2B interaction not fully resolved
    • Whether PYCR1 enzymatic activity or scaffolding mediates this protection unclear
  5. 2018 High

    Metabolic flux analysis in IDH1-mutant cells revealed that PYCR1 serves as a major NADH sink, partially uncoupling TCA activity from the electron transport chain through proline synthesis, establishing its redox-valve function.

    Evidence Isotope tracing, oxygen consumption, and NAD+/NADH ratio measurements in IDH1 R132H cells

    PMID:29562167

    Open questions at the time
    • Generalizability to non-IDH1-mutant contexts was unknown at this time
    • Contribution of PYCR2/PYCRL to total NADH oxidation not separated
  6. 2019 High

    Identification of SIRT3 as the deacetylase and CBP as the acetyltransferase at K228, with acetylation disrupting decamer formation and enzymatic activity, revealed the first post-translational regulatory switch controlling PYCR1 oligomerization.

    Evidence Mass spectrometry for acetylation site, K228 mutagenesis, native gel for decamer, enzymatic activity assay

    PMID:31108370

    Open questions at the time
    • Physiological signals triggering K228 acetylation/deacetylation not defined
    • In vivo metabolic consequences of acetylation-deficient mutants not tested
  7. 2019 Medium

    Lon chaperone was identified as stabilizing PYCR1 protein, and STAT3 was shown to directly interact with PYCR1, linking PYCR1 to EMT and p38/NF-κB signaling beyond its metabolic enzyme role.

    Evidence Co-immunoprecipitation for Lon–PYCR1 and STAT3–PYCR1 interactions; ROS, signaling, and EMT functional assays

    PMID:31606203 PMID:31987921

    Open questions at the time
    • Single Co-IP for each interaction without reciprocal validation in independent labs
    • Whether PYCR1's enzymatic activity is required for STAT3 signaling not dissected
  8. 2020 High

    Direct demonstration that PYCR1 is essential for cancer cell survival under hypoxia by oxidizing NADH to maintain TCA cycle flux generalized the redox-valve concept from IDH1-mutant settings to a broad oxygen-limitation context.

    Evidence Isotope tracing, NADH/NAD+ measurements, 3D spheroid culture, xenograft models with PYCR1 KO

    PMID:35108535

    Open questions at the time
    • Relative contribution of PYCR1 vs. PYCR2 under hypoxia not fully separated
    • Whether normal (non-cancer) tissues rely on this valve in physiological hypoxia unclear
  9. 2020 High

    Crystal structures of PYCR1 with proline analog inhibitors defined the active-site architecture and identified N-formyl-L-proline as a competitive inhibitor that phenocopies PYCR1 knockdown, enabling chemical biology approaches.

    Evidence X-ray crystallography, kinetic inhibition assays, isotope tracing, 3D spheroid growth assay

    PMID:33109600

    Open questions at the time
    • Inhibitor potency (IC50 100 µM) likely insufficient for in vivo use
    • Selectivity against PYCR2/PYCRL not fully characterized
  10. 2021 High

    Genetic redundancy between PYCR1 and PYCR2 was formally established: single knockouts in mice were viable while double knockouts were sub-viable, and both complemented yeast pro3 mutants.

    Evidence Mouse genetics (single and double knockouts), yeast complementation, immunofluorescence localization

    PMID:33734376

    Open questions at the time
    • Tissue-specific expression differences between PYCR1 and PYCR2 not systematically mapped
    • Whether isozymes have distinct substrate preferences in vivo remains open
  11. 2022 High

    PYCR1 was shown to be the critical enzyme for de novo proline synthesis in cancer-associated fibroblasts, where glutamine-derived proline is directly incorporated into tumor collagen; this process is epigenetically upregulated via PDH-derived acetyl-CoA increasing H3K27ac at the PYCR1 locus.

    Evidence Isotope tracing (glutamine→proline→collagen), PYCR1 knockdown in CAFs, ChIP for H3K27ac, xenograft models

    PMID:35760868

    Open questions at the time
    • Whether targeting PYCR1 in CAFs reduces fibrosis independently of tumor context not tested
    • Relative importance of stromal vs. tumor-cell PYCR1 for total tumor proline not quantified
  12. 2023 High

    Discovery that IGF1R phosphorylates PYCR1 at Y135 under hypoxia, directing it to the nucleus where its NAD+ production activates SIRT7-mediated H3K18ac deacetylation at ELK4-target genes, revealed an unexpected moonlighting transcriptional-regulatory function.

    Evidence Co-IP, Y135 mutagenesis, ChIP, enzymatic NAD+ and SIRT7 deacetylase assays, xenograft models

    PMID:37777542

    Open questions at the time
    • Scale of nuclear PYCR1 pool relative to mitochondrial pool not quantified
    • Full set of genes repressed by this pathway not defined genome-wide
  13. 2024 Medium

    Multiple post-translational regulatory inputs were defined: ITPKA phosphorylates PYCR1 at S29 to block Stub1-mediated ubiquitination, BHLHE41 promotes PYCR1 ubiquitination/degradation, and PYCR1-driven lactate production mediates H3K18 lactylation at target gene promoters.

    Evidence Co-IP, kinase assays, ubiquitination assays, metabolomics, ChIP for H3K18 lactylation, xenograft models across glioblastoma, bladder cancer, and HCC

    PMID:38811952 PMID:39170313 PMID:39422696

    Open questions at the time
    • S29 and Y135 phosphorylation interplay not studied
    • Whether lactylation effects are direct consequences of PYCR1 enzymatic activity or indirect metabolic shifts remains unclear
    • BHLHE41 as direct E3 ligase vs. adaptor not distinguished
  14. 2025 Medium

    PYCR1 was found to scaffold EGFR stabilization through USP11 deubiquitinase and to promote TLR/NF-κB signaling via TRAF6/TAK1 interactions, extending its non-enzymatic roles to receptor tyrosine kinase and innate immune signaling.

    Evidence Co-immunoprecipitation, CRISPR KO, ubiquitination assays, PYCR1-IN-1 inhibitor, xenograft models in lung cancer

    PMID:41254241

    Open questions at the time
    • Non-enzymatic scaffolding functions demonstrated only in cancer contexts
    • Structural basis of PYCR1-EGFR-USP11 ternary complex not resolved
    • Independence of scaffolding vs. enzymatic functions not genetically separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how PYCR1's enzymatic (redox) and non-enzymatic (scaffolding/signaling) functions are coordinated; the structural basis for its diverse protein interactions; whether PYCR1 inhibitors can achieve isoform selectivity and in vivo efficacy; and the tissue-specific division of labor between PYCR1, PYCR2, and PYCRL.
  • No potent, selective, in vivo-active PYCR1 inhibitor reported
  • Separation-of-function mutations distinguishing enzymatic from scaffolding roles not generated
  • Tissue-specific metabolic requirements for individual PYCR isozymes not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 7 GO:0060090 molecular adaptor activity 1
Localization
GO:0005739 mitochondrion 5 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 1
Partners
DJ-1EGFRELK4ITPKARRM2BSIRT3STAT3USP11
Complex memberships
PYCR1 decamerPYCR1-EGFR-USP11 complexRRM2B complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 PYCR1 localizes to mitochondria, and loss-of-function mutations cause altered mitochondrial morphology, reduced membrane potential, and increased apoptosis upon oxidative stress in fibroblasts; knockdown in Xenopus and zebrafish caused epidermal hypoplasia and massive apoptosis, linking PYCR1 to mitochondrial function and connective tissue maintenance. Subcellular fractionation/localization, patient fibroblast functional assays, morpholino knockdown in Xenopus and zebrafish Nature genetics High 19648921
2013 DJ-1 (PARK7 gene product) directly binds PYCR1 in vivo and in vitro, co-localizes with PYCR1 in mitochondria, and enhances PYCR1 enzymatic activity in vitro; both proteins operate on the same anti-oxidative stress pathway as shown by non-additive knockdown phenotypes. Co-immunoprecipitation, in vitro binding assay, in vitro enzyme activity assay, co-localization imaging, double knockdown epistasis Biochemical and biophysical research communications High 23743200
2014 Human PYCR1 can act on Δ1-piperideine-6-carboxylate (P6C) to generate L-pipecolic acid, with a Km comparable to its Km for P5C-to-proline conversion, revealing an alternative substrate and role in lysine degradation. In vitro enzyme assay with commercial PYCR1, LC-MS/MS measurement of substrate/product, incubation with patient urine samples Journal of inherited metabolic disease High 24431009
2016 PYCR1 (and PYCR2) were identified as components of RRM2B protein complexes by mass spectrometry; silencing both PYCR1 and PYCR2 abolished RRM2B's anti-oxidative stress activity, caused mitochondrial network fragmentation, and hypersensitivity to oxidative stress, establishing a functional collaboration between these enzymes. Large-scale affinity purification of Flag-RRM2B complexes, mass spectrometry, shRNA knockdown, oxidative stress viability assays, mitochondrial morphology imaging Scientific reports High 26733354
2018 IDH1 R132H mutation perturbs cellular redox homeostasis, driving enhanced NADH oxidation via PYCR1 to synthesize excess glutamine-derived proline; this enhanced PYCR1 activity partially uncouples the electron transport chain from TCA cycle activity by lowering the NADH/NAD+ ratio. Isotope tracing (glutamine-derived proline synthesis), metabolic flux analysis, oxygen consumption measurements, NAD+/NADH ratio measurements in IDH1-mutant cells Cell reports High 29562167
2019 SIRT3 deacetylates PYCR1, with CBP as the acetyltransferase; the major acetylation site is K228. Acetylation of PYCR1 at K228 reduces its enzymatic activity by impairing formation of the PYCR1 decamer, while SIRT3-mediated deacetylation restores activity and promotes cell proliferation. Immunoprecipitation, mass spectrometry, in vitro binding assay, site-directed mutagenesis (K228 acetylation site), enzymatic activity assay, native gel electrophoresis for decamer formation Neoplasia High 31108370
2019 Mitochondrial Lon chaperone stabilizes PYCR1 as a client protein; Lon-mediated PYCR1 upregulation induces mitochondrial ROS and promotes EMT via ROS-dependent p38 and NF-κB signaling. Co-immunoprecipitation (Lon-PYCR1 interaction), ROS measurement, signaling pathway western blots, EMT assays Cancer letters Medium 31987921
2019 PYCR1 directly interacts with STAT3 as demonstrated by Co-IP assay; PYCR1 knockdown inhibits STAT3-mediated p38 MAPK and NF-κB signaling, and STAT3 overexpression partially reverses PYCR1 knockdown effects on proliferation, drug resistance, and EMT in colorectal cancer cells. Co-immunoprecipitation, siRNA knockdown, western blot, MTT assay Biochemical and biophysical research communications Medium 31606203
2020 In hypoxic conditions, mitochondrial PYCR1 activity is increased to oxidize NADH by synthesizing proline, which allows continued TCA cycle activity; loss of PYCR1 leads to increased hypoxia in vivo and in 3D culture and widespread cell death, demonstrating PYCR1 as a critical redox valve under oxygen-limiting conditions. Isotope tracing, NADH/NAD+ measurement, 3D spheroid culture, xenograft models, PYCR1 knockdown/knockout Cell reports High 35108535
2020 In crystallo screening identified five proline analog inhibitors of human PYCR1; the most potent, N-formyl-L-proline (NFLP, IC50 = 100 µM), competitively inhibits P5C binding and induces conformational changes including 1 Å translation of an active-site α-helix; NFLP phenocopies PYCR1 knockdown by inhibiting de novo proline biosynthesis and spheroidal growth in cancer cells. X-ray crystallography, kinetic inhibition assays, stable isotope tracing in MCF10A H-RASV12 cells, 3D spheroid growth assay The Journal of biological chemistry High 33109600
2021 FTO demethylase decreases N6-methyladenosine (m6A) methylation on PYCR1 mRNA, stabilizing the PYCR1 transcript; USP18 deubiquitinase upregulates FTO protein levels, establishing a USP18/FTO/PYCR1 regulatory axis in bladder cancer. m6A methylation assays, mRNA stability assays, western blot, co-immunoprecipitation, functional cancer cell assays Aging Medium 33461172
2021 PYCR1 and PYCR2 are both localized in mitochondria of fibroblasts; Pycr1 and Pycr2 are functionally redundant P5C reductases, as both complemented yeast pro3 mutants; double knockout mice were sub-viable, while single knockouts were viable, demonstrating genetic redundancy in proline biosynthesis. Mitochondrial localization by immunofluorescence in fibroblasts, yeast complementation assay (pro3 mutant), mouse genetics (single and double knockouts) Genetics High 33734376
2022 PYCR1 is a key enzyme for proline synthesis in cancer-associated fibroblasts (CAFs), where glutamine-derived proline is newly synthesized and incorporated into tumor collagen; both collagen production and PYCR1 expression in CAFs are epigenetically upregulated by pyruvate dehydrogenase-derived acetyl-CoA increasing H3K27ac levels at relevant gene loci. Isotope tracing (glutamine-to-proline-to-collagen flux), PYCR1 knockdown in CAFs, xenograft tumor models, ChIP for acetyl-CoA/H3K27ac Nature metabolism High 35760868
2022 PYCR1 promotes colorectal cancer resistance to 5-fluorouracil by inhibiting ferroptosis and apoptosis through upregulation of SLC25A10; PYCR1 overexpression inhibits lipid ROS production. Ferroptosis/apoptosis assays, ROS measurement, SLC25A10 expression analysis, ferroptosis inhibitor/inducer experiments, in vivo tumor growth Human cell Medium 36104652
2022 SENP3 promotes STAT3 deSUMOylation, increasing STAT3 protein levels and nuclear translocation; nuclear STAT3 directly binds the PYCR1 gene promoter and transcriptionally upregulates PYCR1 expression in bladder cancer. Co-immunoprecipitation (SENP3-STAT3), ChIP for STAT3 at PYCR1 promoter, western blot, functional cancer cell assays Aging Medium 36227136
2023 Under hypoxia, nuclear IGF1R phosphorylates PYCR1 at Tyrosine 135; this phosphorylation promotes PYCR1 binding to ELK4 and recruitment to ELK4-target gene promoters; PYCR1-catalyzed NAD+ production in the nucleus stimulates SIRT7 deacetylation of H3K18ac, leading to transcriptional repression that supports tumor growth. Co-immunoprecipitation (PYCR1-ELK4, PYCR1-IGF1R), site-directed mutagenesis (Y135), ChIP, enzymatic NAD+ production assay, SIRT7 deacetylase activity assay, xenograft models Nature communications High 37777542
2023 PYCR1 interacts with EGFR by co-immunoprecipitation in bladder cancer cells; PYCR1-EGFR interaction activates the EGFR/PI3K/AKT signaling pathway to promote aerobic glycolysis and malignant cell behaviors; EGFR inhibitor CL-387785 attenuated PYCR1 overexpression effects without altering PYCR1 expression. Co-immunoprecipitation, EGFR inhibitor rescue experiment, aerobic glycolysis assays, xenograft model International journal of oncology Medium 37293856
2024 BHLHE41 directly interacts with PYCR1 by co-immunoprecipitation and promotes PYCR1 ubiquitination and proteasomal degradation, thereby decreasing its stability and inactivating the PI3K/AKT signaling pathway to suppress bladder cancer. Co-immunoprecipitation, ubiquitination assay, western blot, functional cancer cell assays in vitro and in vivo European journal of medical research Medium 38811952
2024 ITPKA phosphorylates PYCR1 at Serine 29; this phosphorylation inhibits Stub1 E3 ligase-mediated ubiquitination of PYCR1, thereby stabilizing PYCR1 protein levels and contributing to oncogenic function in glioblastoma. Co-immunoprecipitation (ITPKA-PYCR1), kinase phosphorylation assay at S29, ubiquitination assay, Stub1 interaction studies, in vivo xenograft Heliyon Medium 39170313
2024 PYCR1 knockout in hepatocellular carcinoma cells inhibits glycolysis and reduces H3K18 lactylation at the IRS1 promoter, thereby suppressing IRS1 transcription; metabolomics and ChIP confirmed that PYCR1-driven lactate production mediates this epigenetic regulation. PYCR1 knockout, metabolomics, ChIP for H3K18 lactylation at IRS1 promoter, transcriptome sequencing, xenograft model Clinical and translational medicine Medium 39422696
2024 SMYD2 upregulates PYCR1 expression through H3K4 trimethylation (H3K4me3) at the PYCR1 locus; PYCR1 in turn activates the PINK1/Parkin mitophagy pathway to support bladder cancer stem cell stemness maintenance. ChIP for H3K4me3, SMYD2/PYCR1 siRNA knockdown, mitophagy assay (Mito-Tracker, LC3B), sphere formation assay, nude mouse xenograft International journal of oncology Medium 40341538
2024 A micropeptide TREMP encoded by lincR-PPP2R5C localizes to mitochondria and interacts with PYCR1 by co-immunoprecipitation; TREMP-PYCR1 interaction enhances glycolysis in Th2 cells and promotes Th2 cell differentiation; PYCR1 knockout mice showed suppressed Th2 differentiation and reduced allergic airway inflammation. Co-immunoprecipitation, CRISPR/Cas9 knockout mice (TREMP and PYCR1), glycolysis measurement, flow cytometry for Th2 differentiation, HDM allergy model Allergology international Medium 39025723
2024 A missense mutation (p.Ala187Thr) in PYCR1 impairs PYCR1 enzymatic activity in vitro; 3D structural modeling showed the mutation alters hydrogen bonding causing protein misfolding, establishing a direct genotype-enzyme activity link. Site-directed mutagenesis, in vitro enzyme activity assay, 3D structural modeling Molecular genetics and genomics Medium 39172257
2021 Human PYCR1 catalyzes NAD(P)H-dependent reduction of P5C to L-proline as its canonical enzymatic function; three human isozymes (PYCR1, PYCR2, PYCRL) are encoded by distinct genes and transfer oxidizing potential across the mitochondrion. Biochemical characterization (review consolidating enzymatic studies) Amino acids Medium 34291342
2025 PYCR1 stabilizes EGFR by forming a complex with EGFR and the deubiquitinase USP11, enhancing EGFR deubiquitination and stability; PYCR1 also promotes TLR signaling by interacting with TRAF6, TAK1, ECSIT, and TAB2, facilitating their ubiquitination and NF-κB activation in lung cancer. Co-immunoprecipitation, CRISPR-Cas9 knockout, ubiquitination assays, PYCR1-IN-1 inhibitor treatment, xenograft models Experimental & molecular medicine Medium 41254241
2025 Under hypoxia, PYCR1 enhances glycolysis and lactate production, increasing H3K18 lactylation levels, which upregulates SLC6A14 transcription to promote glutamine catabolism and bladder cancer progression; in vivo experiments confirmed the PYCR1/H3K18la/SLC6A14 axis. Hypoxia cell culture, glycolysis/lactate assays, H3K18 lactylation western blot, SLC6A14 expression analysis, xenograft and metastasis models Cancer biology & therapy Medium 40808274
2025 FOXA1 acts as an upstream transcriptional activator of PYCR1 (validated by dual-luciferase and ChIP assays); PYCR1 overexpression activates autophagy in lung adenocarcinoma cells, dampening CD8+ T cell antitumor immune response. Dual-luciferase reporter assay, ChIP assay, autophagy assays, flow cytometry for CD8+ T cell function, LDH cytotoxicity assay, mouse tumor model Cancer immunology, immunotherapy Medium 40848149

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutations in PYCR1 cause cutis laxa with progeroid features. Nature genetics 177 19648921
2022 Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nature metabolism 129 35760868
2020 Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis. Cancer letters 117 31987921
2017 Knockdown of PYCR1 inhibits cell proliferation and colony formation via cell cycle arrest and apoptosis in prostate cancer. Medical oncology (Northwood, London, England) 77 28078560
2018 Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis. Cell reports 72 29562167
2016 PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress. Scientific reports 65 26733354
2022 Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. Cell reports 57 35108535
2019 Knockdown of PYCR1 inhibits proliferation, drug resistance and EMT in colorectal cancer cells by regulating STAT3-Mediated p38 MAPK and NF-κB signalling pathway. Biochemical and biophysical research communications 55 31606203
2018 PYCR1 promotes the progression of non-small-cell lung cancer under the negative regulation of miR-488. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 30605882
2013 Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Molecular genetics and metabolism 51 24035636
2019 SIRT3 regulates cancer cell proliferation through deacetylation of PYCR1 in proline metabolism. Neoplasia (New York, N.Y.) 49 31108370
2019 PYCR1 interference inhibits cell growth and survival via c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathway in hepatocellular cancer. Journal of translational medicine 49 31619254
2021 Dysregulation of USP18/FTO/PYCR1 signaling network promotes bladder cancer development and progression. Aging 48 33461172
2020 PYCR1 knockdown inhibits the proliferation, migration, and invasion by affecting JAK/STAT signaling pathway in lung adenocarcinoma. Molecular carcinogenesis 48 32133692
2024 PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification. Clinical and translational medicine 45 39422696
2020 RAC3 Promotes Proliferation, Migration and Invasion via PYCR1/JAK/STAT Signaling in Bladder Cancer. Frontiers in molecular biosciences 44 33062641
2013 DJ-1 cooperates with PYCR1 in cell protection against oxidative stress. Biochemical and biophysical research communications 43 23743200
2021 P5C as an Interface of Proline Interconvertible Amino Acids and Its Role in Regulation of Cell Survival and Apoptosis. International journal of molecular sciences 37 34769188
2008 Tailoring the structure of aminobisphosphonates to target plant P5C reductase. Journal of agricultural and food chemistry 35 18399639
2021 PYCR1 promotes bladder cancer by affecting the Akt/Wnt/β-catenin signaling. Journal of bioenergetics and biomembranes 30 33689096
2019 A fragment-like approach to PYCR1 inhibition. Bioorganic & medicinal chemistry letters 30 31362921
2010 The phenotype caused by PYCR1 mutations corresponds to geroderma osteodysplasticum rather than autosomal recessive cutis laxa type 2. American journal of medical genetics. Part A 29 21204221
2020 In crystallo screening for proline analog inhibitors of the proline cycle enzyme PYCR1. The Journal of biological chemistry 28 33109600
2014 Human pyrroline-5-carboxylate reductase (PYCR1) acts on Δ(1)-piperideine-6-carboxylate generating L-pipecolic acid. Journal of inherited metabolic disease 28 24431009
2007 Plant P5C reductase as a new target for aminomethylenebisphosphonates. Journal of agricultural and food chemistry 26 17474756
2019 The clinical significance of PYCR1 expression in renal cell carcinoma. Medicine 25 31305441
2023 Exosomes from PYCR1 knockdown bone marrow mesenchymal stem inhibits aerobic glycolysis and the growth of bladder cancer cells via regulation of the EGFR/PI3K/AKT pathway. International journal of oncology 24 37293856
2011 Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome. American journal of medical genetics. Part A 24 22052856
2023 IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia. Nature communications 23 37777542
2022 The role of PYCR1 in inhibiting 5-fluorouracil-induced ferroptosis and apoptosis through SLC25A10 in colorectal cancer. Human cell 22 36104652
2021 MiR-328-3p inhibits lung adenocarcinoma-genesis by downregulation PYCR1. Biochemical and biophysical research communications 22 33706104
2021 Deciphering the effects of PYCR1 on cell function and its associated mechanism in hepatocellular carcinoma. International journal of biological sciences 21 34239351
2018 Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. Human genetics 21 30450527
2011 A novel mutation in PYCR1 causes an autosomal recessive cutis laxa with premature aging features in a family. American journal of medical genetics. Part A 21 21567914
2022 PYCR1 regulates glutamine metabolism to construct an immunosuppressive microenvironment for the progression of clear cell renal cell carcinoma. American journal of cancer research 20 36119844
2019 Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities. Cells 20 31091804
2023 PYCR1 promotes the malignant progression of lung cancer through the JAK-STAT3 signaling pathway via PRODH-dependent glutamine synthesize. Translational oncology 19 37018868
2019 PYCR1 is Associated with Papillary Renal Cell Carcinoma Progression. Open medicine (Warsaw, Poland) 17 31428683
2022 Survival and clinicopathological significance of PYCR1 expression in cancer: A meta-analysis. Frontiers in oncology 14 36119513
2021 Phenyl-substituted aminomethylene-bisphosphonates inhibit human P5C reductase and show antiproliferative activity against proline-hyperproducing tumour cells. Journal of enzyme inhibition and medicinal chemistry 14 34107832
2021 MiR-1207-5p targets PYCR1 to inhibit the progression of prostate cancer. Biochemical and biophysical research communications 13 34461437
2021 MicroRNA hsa-miR-150-5p inhibits nasopharyngeal carcinogenesis by suppressing PYCR1 (pyrroline-5-carboxylate reductase 1). Bioengineered 12 34696668
2022 SENP3 affects the expression of PYCR1 to promote bladder cancer proliferation and EMT transformation by deSUMOylation of STAT3. Aging 11 36227136
2021 Genetic analysis of Pycr1 and Pycr2 in mice. Genetics 11 33734376
2021 Isozymes of P5C reductase (PYCR) in human diseases: focus on cancer. Amino acids 11 34291342
2021 Knockdown of PYCR1 suppressed the malignant phenotype of human hepatocellular carcinoma cells via inhibiting the AKT pathway activation. Reproductive biology 9 34271243
2024 Crosstalk between FTH1 and PYCR1 dysregulates proline metabolism and mediates cell growth in KRAS-mutant pancreatic cancer cells. Experimental & molecular medicine 8 39294443
2022 Epigenetic modification facilitates proline synthase PYCR1 aberrant expression in gastric cancer. Biochimica et biophysica acta. Gene regulatory mechanisms 8 35654390
2022 miR-150-5p inhibits nasopharyngeal cancer genesis by suppressing PYCR1. The American journal of the medical sciences 8 35718122
2022 Low-dose radiation exaggerates HFD-induced metabolic dysfunction by gut microbiota through PA-PYCR1 axis. Communications biology 8 36088469
2024 Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography. Journal of chemical information and modeling 7 38411104
2023 LINC01123 acts as an oncogenic driver in lung adenocarcinoma by regulating the miR-4766-5p/PYCR1 axis. Histology and histopathology 7 36994814
2022 CRIF1 promotes the progression of non-small-cell lung cancer by SIRT3- mediated deacetylation of PYCR1. Journal of molecular histology 7 35716330
2024 Pro-tumorigenic activity of PYCR1 in gastric cancer through regulating the PI3K/AKT signaling. Heliyon 6 38455525
2024 Screening a knowledge-based library of low molecular weight compounds against the proline biosynthetic enzyme 1-pyrroline-5-carboxylate 1 (PYCR1). Protein science : a publication of the Protein Society 6 39133178
2016 Clusterin and Pycr1 alterations associate with strain and model differences in susceptibility to experimental pancreatitis. Biochemical and biophysical research communications 5 27939882
2025 Mechanism of SMYD2 promoting stemness maintenance of bladder cancer stem cells by regulating PYCR1 expression and PINK1/Parkin mitophagy pathway. International journal of oncology 4 40341538
2025 Hypoxia-induced PYCR1 regulates glycolysis and histone lactylation to promote bladder cancer progression and metastasis via SLC6A14/Glutamine metabolism. Cancer biology & therapy 4 40808274
2024 BHLHE41 inhibits bladder cancer progression via regulation of PYCR1 stability and thus inactivating PI3K/AKT signaling pathway. European journal of medical research 4 38811952
2024 PYCR1 expresses in cancer-associated fibroblasts and accelerates the progression of C6 glioblastoma. Histology and histopathology 3 38826151
2024 A micropeptide TREMP encoded by lincR-PPP2R5C promotes Th2 cell differentiation by interacting with PYCR1 in allergic airway inflammation. Allergology international : official journal of the Japanese Society of Allergology 3 39025723
2022 Circ_0000705 facilitates proline metabolism of esophageal squamous cell carcinoma cells by targeting miR-621/PYCR1 axis. Discover oncology 3 35731336
2025 Effect and mechanism of PYCR1 on biological function of hepatocellular carcinoma cells under hypoxia. Discover oncology 2 40542176
2024 Please, carefully, pass the P5C. Journal of experimental botany 2 38307518
2024 PYCR1 regulates TRAIL‑resistance in non‑small cell lung cancer cells by regulating the redistribution of death receptors. Oncology letters 2 38549801
2024 ITPKA phosphorylates PYCR1 and promotes the progression of glioma. Heliyon 2 39170313
2022 Metabolomic and transcriptomic studies of improvements in myocardial infarction due to Pycr1 deletion. Journal of cellular and molecular medicine 2 36495058
2025 The Proline Dehydrogenase Gene CsProDH1 Regulates Homeostasis of the Pro-P5C Cycle Under Drought Stress in Tea Plants. International journal of molecular sciences 1 40243904
2025 The key enzyme PYCR1 in proline metabolism: a dual driver of cancer progression and fibrotic remodeling. Journal of enzyme inhibition and medicinal chemistry 1 40891362
2025 Crystallographic fragment screening reveals new starting points for PYCR1 inhibitor design. Bioorganic chemistry 1 41016381
2022 Functional Characterization of Saccharomyces cerevisiae P5C Reductase, the Enzyme at the Converging Point of Proline and Arginine Metabolism. Microorganisms 1 36296354
1991 Possible involvement of a L-delta 1-pyrroline-5-carboxylate (P5C) reductase in the synthesis of proline in Desulfovibrio desulfuricans Norway. Biochemical and biophysical research communications 1 1898390
2026 Integrating virtual screening and molecular dynamics simulations to identify emodin as a PYCR1 inhibitor modulating docetaxel sensitivity in prostate cancer. Journal of enzyme inhibition and medicinal chemistry 0 41665114
2026 Multi-omics analyses related to mitochondria and ageing in triple-negative breast cancer implicate PYCR1 potentiates tumor progression. Cancer cell international 0 41749247
2026 PYCR1 Downregulation Induces Autophagy Dependent Apoptosis Through Inhibiting PI3K/AKT/mTOR Axis in Human Hepatocellular Carcinoma Cells. Analytical cellular pathology (Amsterdam) 0 41810929
2026 [Research Progress on the Role and Mechanisms of PYCR1 
in Tumorigenesis and Progression]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 41975648
2025 PYCR1 Promotes Esophageal Squamous Cell Carcinoma by Interacting With EGFR to Affecting the PI3K/Akt/mTOR Signaling Pathway. The journal of gene medicine 0 40102683
2025 [A pan-cancer analysis of PYCR1 and its predictive value for chemotherapy and immunotherapy responses in bladder cancer]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 40294939
2025 9-Deazaadenosine directly binds PYCR1 and inhibits cancer cell proliferation through disruption of NAD+ metabolism. Translational oncology 0 40706441
2025 The transcription factor FOXA1 upregulates PYCR1-mediated autophagy to suppress antitumor immunity in lung adenocarcinoma. Cancer immunology, immunotherapy : CII 0 40848149
2025 PYCR1 inhibition in bone marrow stromal cells enhances bortezomib sensitivity in multiple myeloma cells by altering their metabolism. Molecular oncology 0 40932053
2025 Glutamine metabolism reprogramming promotes bladder cancer progression via PYCR1: a multi-omics and functional validation study. Journal of translational medicine 0 41233804
2025 PYCR1 drives lung cancer progression through functional interactions with EGFR and TLR signaling pathways. Experimental & molecular medicine 0 41254241
2024 Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2. Molecular genetics and genomics : MGG 0 39172257
2024 Successful Reduction of a Dislocated Hip Joint in a Patient With Cutis Laxa From a PYCR1 Mutation: Case Report. JBJS case connector 0 39739984